Shi, L., Zhang, X., Golhar, R., Otieno, F. G., He, M., Hou, C., Kim, C., Keating, B., Lyon, G. J., Wang, K., Hakonarson, H. (2013) Whole-genome sequencing in an autism multiplex family. Molecular Autism, 4 (1). p. 8. ISSN 2040-2392 (Electronic)
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Abstract
BACKGROUND: Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental disorders that affect 1 in 88 children in the US. Previous exome sequencing studies on family trios have implicated a role for rare, de-novo mutations in the pathogenesis of autism. METHODS: To examine the utility of whole-genome sequencing to identify inherited disease candidate variants and genes, we sequenced two probands from a large pedigree, including two parents and eight children. We evaluated multiple analytical strategies to identify a prioritized list of candidate genes. RESULTS: By assuming a recessive model of inheritance, we identified seven candidate genes shared by the two probands. We also evaluated a different analytical strategy that does not require the assumption of disease model, and identified a list of 59 candidate variants that may increase susceptibility to autism. Manual examination of this list identified ANK3 as the most likely candidate gene. Finally, we identified 33 prioritized non-coding variants such as those near SMG6 and COQ5, based on evolutionary constraint and experimental evidence from ENCODE. Although we were unable to confirm rigorously whether any of these genes indeed contribute to the disease, our analysis provides a prioritized shortlist for further validation studies. CONCLUSIONS: Our study represents one of the first whole-genome sequencing studies in autism leveraging a large family-based pedigree. These results provide for a discussion on the relative merits of finding de-novo mutations in sporadic cases versus finding inherited mutations in large pedigrees, in the context of neuropsychiatric and neurodevelopmental diseases.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > mental disorders diseases & disorders > mental disorders > personality disorders diseases & disorders > mental disorders > personality disorders > autism bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > copy number variants Investigative techniques and equipment > assays > whole genome sequencing |
| CSHL Authors: | |
| Communities: | CSHL labs > Lyon lab |
| Depositing User: | Matt Covey |
| Date: | 2013 |
| Date Deposited: | 22 May 2013 17:45 |
| Last Modified: | 17 Sep 2013 19:15 |
| PMCID: | PMC3642023 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/28321 |
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